Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage

Harikanth Venkannagari, Patricia Verheugd, Jarkko Koivunen, Teemu Haikarainen, Ezeogo Obaji, Yashwanth Ashok, Mohit Narwal, Taina Pihlajaniemi, Bernhard Lüscher, Lari Lehtiö

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Members of the human diphtheria toxin-like ADP-ribosyltransferase (ARTD or PARP) family play important roles in regulating biological activities by mediating either a mono-ADP-ribosylation (MARylation) of a substrate or a poly-ADP-ribosylation (PARylation). ARTD10/PARP10 belongs to the MARylating ARTDs (mARTDs) subfamily, and plays important roles in biological processes that range from cellular signaling, DNA repair, and cell proliferation to immune response. Despite their biological and disease relevance, no selective inhibitors for mARTDs are available. Here we describe a small-molecule ARTD10 inhibitor, OUL35, a selective and potent inhibitor for this enzyme. We characterize its selectivity profile, model its binding, and demonstrate activity in HeLa cells where OUL35 rescued cells from ARTD10 induced cell death. Using OUL35 as a cell biology tool we show that ARTD10 inhibition sensitizes the cells to the hydroxyurea-induced genotoxic stress. Our study supports the proposed role of ARTD10 in DNA-damage repair and provides a tool compound for selective inhibition of ARTD10-mediated MARylation.

Original languageEnglish (US)
Pages (from-to)1251-1260
Number of pages10
JournalCell Chemical Biology
Volume23
Issue number10
DOIs
StatePublished - Oct 20 2016

Keywords

  • ADP-ribosylation
  • ARTD100
  • DNA repair
  • PARP10
  • chemical probe
  • inhibitor

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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    Venkannagari, H., Verheugd, P., Koivunen, J., Haikarainen, T., Obaji, E., Ashok, Y., Narwal, M., Pihlajaniemi, T., Lüscher, B., & Lehtiö, L. (2016). Small-Molecule Chemical Probe Rescues Cells from Mono-ADP-Ribosyltransferase ARTD10/PARP10-Induced Apoptosis and Sensitizes Cancer Cells to DNA Damage. Cell Chemical Biology, 23(10), 1251-1260. https://doi.org/10.1016/j.chembiol.2016.08.012